Modernization, collaboration, and innovation are some of the most important concepts in the drug development sector due to how increasingly complex the therapeutic landscape is becoming. Despite high levels of investment being poured into the biopharma industry each year, many challenges that arise from the use of traditional models and processes still exist within drug development. For example, the emergence of artificial intelligence (AI) can find potential new molecules a thousand times faster than existing models, yet patients are not able to access the benefits because of bottlenecks in the development process, such as project management and collecting data (1).

However, hope is on the horizon as novel solutions and improvements aimed at benefitting the drug development process with the right framework are coming to the fore. Focusing on the patient, digital and technology enablement, and advanced analytics are a few ways that research and development have been given a kickstart in transforming traditional approaches; although, this is just the beginning of a long journey toward a more dynamic, beneficial drug development process (2).

Traditional drug development is a cost and time-intensive process, which has caused an array of issues in the past. Ted Broering, president of early clinical and bioanalytical solutions at ICON, mentions that apart from the standard objective of establishing drug safety in healthy volunteers, early phase trials are also on the critical pathway of collating data to determine if the drug holds potential for further development and label expansion. In terms of increasing costs and pressures for smaller timelines, he explains how early phase study designs have become the proverbial “kitchen sink” with multiple questions being asked that help determine the development pathway.

“These early protocols are now being written as ‘adaptive’ designs, allowing flexibility to adjust dose levels, to add or clarify sampling timepoints based on emerging data, and trial expansion if needed,” Broering says. “Long gone are the days of a simple ascending dose first in human (FIH) trial, now we can execute adaptive combination designs that would have once been conducted as four different trials—single ascending dose, multiple ascending dose, food effect, and patient arm all in one umbrella protocol.”

In terms of downstream processing, Heidi Jones, market development manager, Process Chromatography at Bio-Rad Laboratories, explains that column packing can be a very time consuming, resource intensive activity, requiring specialized equipment and training. “Additionally, variability in packing quality can lead to inconsistent lot-to-lot purification results,” she says. “Prepacked columns (packed with the appropriate resins, i.e., affinity, ion exchange, mixed mode, and so forth) can mitigate many of these issues and constraints to efficiency. [These prepacked options] provide consistent, FDA compliant columns that meet specific quality criteria” (3).

AI/machine learning types of applications have made a significant impact for analyzing large, linked data sets for accelerating drug development while reducing costs, according to Philip Russmeyer, founder and CEO of FITFILE, which was founded in 2020 by Philip to help deliver safer, faster, and better profiles of record-level health. He further elaborated on recent advances in genomic sequencing and clinical trials, as pharmaceutical companies are increasingly collaborating with academic institutions, government agencies, and non-profit organizations to share resources and non-commercially
sensitive information.

“Furthermore, advances in genomic sequencing are enabling more targeted drug development, facilitating faster drug approvals,” Russmeyer says. “For clinical trials, with record linkage and advanced analytics the right patients can now be quickly and efficiently identified and recruited (4), and site selection has become much easier with the arrival of more granular and dependable information” (5).

Russmeyer also emphasizes that regulatory bodies, like the UK Medicines and Healthcare products Regulatory Agency (MHRA), have recently implemented new policies to streamline the drug approval process. “Under the latest MHRA framework, clinical trials application processes in the UK will be more proportionate, streamlined, and flexible without compromising on safety,” he says.

When asked about the 505(b)(2) pathway, Robert Lee, president at Lubrizol Life Science Health in the contract development and manufacturing organization (CDMO) division, points out that this strategy is effective at accelerating the process, repurposing drugs for different routes of administration, or developing a differentiated dosage form. “Differentiation can be in terms of better biological performance (i.e., lower dose) or a safer product (i.e., lower toxicity or reduced off target exposure). The safety packages are already out there for approved drugs, so there are fewer hurdles to overcome, shrinking the cost and development time significantly,” he explains. “One potential approach to achieving a successful 505(b)(2) repurposing is by utilizing novel excipients in combination with the existing, marketed APIs to make a product that is suitable for new routes of administration.”

Bottlenecks in data and project areas, along with other hurdles, can impact a drug development process by weeks, months, or years, and its overall influence on the lifespan of a drug development program can magnify more inefficiencies. Delays, added costs, and more can create less availability of new and innovative treatments for patients (1).

Tomasz Kostrzewski, PhD, VP, science and technology at CN Bio Innovations, explains that 90% of drugs that enter clinical trials fail to become approved medicines, and to avoid a “rubbish in–rubbish out” scenario, the problem needs to be addressed ahead of this phase before a significant reduction in attrition rates begins. “Prior drug development decisions regarding target and candidate selection are based upon in-vitro and in-vivo animal models with limited translational relevance as they either lack human complexity, or relevance. Recreating the human immune system poses a particularly significant challenge,” he says. “Within the development phase, animal studies are widely used to further evaluate the safety and efficacy of a drug candidate, to determine optimal dose/schedule for clinical trials and to inform regulatory submissions, but again, interspecies differences mean that the data from these studies often fail to translate into human outcomes.”

Kostrzewski also discusses how drug discovery is moving away from small molecule discovery toward newer drug classes, such as cell and gene therapies, antibodies, and peptides. “This new wave of therapeutics is the future; however, they provide new challenges due to their human-specific mechanism of action which [means] animals [are] less suited for their testing,” he says. “Non-human primates offer a solution, but their use is strictly regulated, costly, unsustainable, and ethically undesirable.”

Supply chain issues are a major hurdle facing early drug development, and Lee describes how challenging backlogs have been seen in the contract business, like contract research organizations (CROs), CDMOs, and API manufacturers. “If your pool of potential service providers shrinks, that’s going to impact the quality and timing of your development program,” he says. “Additionally, there are issues surrounding funding. It’s harder to get capital now, which can add extra pressure when developing new drugs.”

Jones comments that successfully expressing and purifying a potential drug therapeutic can be a challenge in the early drug development process. “Once a viable expression and production system is identified, developing an adequate, (and preferably) robust orthogonal purification process can be challenging and can become the bottleneck in moving a potential drug therapeutic to the next stage of the development process (i.e., for initial stability studies, in-vitro assays, analytics), particularly if expression titers are low, or if the therapeutic is prone to clipping or degradation,” she says.

Interestingly, Broering does not believe that there are specific bottlenecks per se, but that there is a growing demand within industry for early phase studies with a small group of patients as opposed to healthy volunteers. “These early phase patient studies can estimate the pharmacokinetic (PK) levels to see if the drug has the same profile as in healthy subjects and can also inform the design of later phase patient trials,” he comments. “Sponsors are looking for these studies for data comparison to be run under a Phase I setting with very tight timepoint collections which can be challenging.”

There are several approaches from different areas that the biopharmaceutical industry can take to alleviate the hurdles and avoid future issues that may have hindered companies in the past. According to Russmeyer, health data platforms have the capacity to help solve the “data problem” that drug developers are running into.

“If the right secure platform is deployed, approved persons can access a huge wealth of clinical and non-clinical health data linked at the record-level from a single point of access. This enables researchers to understand complete health profiles and how they relate to the efficacy of new drugs in patient populations over time, so they can more easily measure the impact and monitor safety,” Russmeyer explains. “These platforms’ privacy-preserving technology and high security standards help ensure the safe use of data to drive progress in the industry, ultimately improving outcomes for patients.”

For Kostrzewski, organ-on-a-chip (OOC) technology can help to ease these hurdles by enabling researchers to recreate models of human physiology and disease in the laboratory. “These lab-grown miniature organs and tissues are comprised of physiologically-relevant combinations of primary human cells grown on scaffolds to support 3D growth. They are perfused by media to mimic the blood stream and importantly, can incorporate elements of both the human adaptive and innate immune system,” he explains. “OOC models function and respond to therapeutics in a similar way to humans and deliver clinically relevant end points to facilitate the translation of data between the lab and clinic. It is possible to link models together to simulate processes such as drug absorption and metabolism, or to understand interactions between organs, such as inflammation, which drive disease and cause unexpected toxicities. Importantly, they offer a path forward for the discovery and development of new modality drugs with human specific modes of action in combination with other non-animal-based new alternative methodologies (NAMS) such as in-silico modeling.”

Kostrezewski adds that, going forward, he anticipates that OOC will start to reduce our reliance on costly and expensive animal studies in late discovery early development. “OOC use additionally enables the exploration of a greater experimental space, enabling study design to be fine-tuned to maximize their efficiency and reduce the number of animals used,” he says. “Further along the pipeline within development, OOC can even be used to confirm, or query the results generated in animal studies to overcome concerns about interspecies differences and enable researchers to either proceed into clinical trials with more confidence, or to reengineer drugs to remove any unwanted effects.”

According to Lee, novel excipients are perfect for the 505(b)(2) pathway to reduce both time and cost to approval. “With 505(b)(2) you want to have a differentiated, better dosage form than what was commercially available, and maybe a different route of administration. Novel excipients offer fresh intellectual property and can be offered on an exclusive basis to help protect the asset,” he explains. “Particularly in the early stages of drug development, selecting a CDMO with a wide range of capabilities and expertise can improve the probability and accelerate the process of reaching the target product profile. Flexibility is also important, particularly with high value products like biologics, you need to make sure there are no lower limitations on batch size.”

A variety of chromatography tools are available to assist drug developers in the purification process, Jones mentions. “From 96-well plate format for resin scouting, to process scale prepacked columns, researchers can perform design of experiment [DOE] studies through to process scale-up while eliminating the time spent manually packing columns, along with the need for specialized equipment, specialized training, as well as reducing packing variation, given that prepacked columns are required to adhere to specific and stringent quality controls,” she says (3).

Patient-centricity has been driving change within the drug development area for some time, and it continues to grow in importance. Technical development activities, like digitization of clinical trials, can help achieve this goal and accelerate the overall drug development process.

Ute Berger, president of development and commercialization solutions at ICON, explains the concept of digitization of clinical trials in more detail, which, if executed in the right way, has the potential to improve patient-centricity of trials and reduce potential failures. “Decentralized clinical trials have been shown to overcome some of the long-term industry challenges in drug development that have had a significant impact in timelines, such as patient recruitment and retention,” she elaborates. “According to Tufts Center for the Study of Drug Development [CSSD] 41% of clinical trials fail to meet planned enrollment estimates and other industry figures suggest 30% patient drop out from trials” (6).

Berger further explains that there are some basic fundamentals in ensuring the technology is patient centric, including: ensuring the study design and technology interaction is developed to reduce rather than increase patient burden; ensuring patients have the option rather than making it mandatory to be monitored remotely, whether that is through digital health technologies or data capture at in-home visits; and most importantly, providing appropriate support both technical and clinical through specialized concierge services. “Concierge services can help with scheduling, welcoming patients, managing consent, responding to patient concerns, collecting reported events or retrieving equipment, all which increase patient satisfaction and lead to higher retention, to avoid delays,” she says.

The most important pillar of patient-centricity for Russmeyer is bringing the voices of real patients into the earliest phases of technical development, from study design to formulation and delivery decisions. “Analyzing data from patient focus groups and surveys will support drug companies to approach the technical development with a better understanding of how to improve patient engagement and participation in clinical trials, and how to improve adherence to and outcomes from new medications,” he says. “In addition, using safely anonymized data united across sources in a way that doesn’t require consent can fold in a patient-centric approach at a much larger, clinically valuable scale.”

Lee mentions that one might think there is enough of a challenge to commercialize a new molecular entity via a 505(b)(1) path so that patients can receive treatment as soon as possible without looking at novel delivery systems. However, new technologies are emerging all the time, with a major focus on patient-centricity upfront. “Drug–device combination products are a great example, for instance in the case of an autoinjector, where you could potentially self-administer at home, saving time by not having to go to the doctor’s office,” he explains. “Many drug developers are looking to new devices to overcome patient challenges of conventional delivery, and in fact we have an established department dedicated to drug-eluting devices such as vaginal rings, intraocular implants, and subcutaneous implants.”

More automated solutions, such as AI, are being widely implemented to improve efficiencies. The value of these types of technologies in the biopharmaceutical drug development area has become a tool for collaboration and innovation for many.

Russmeyer explains how AI can be deployed to analyze vast data sets much more quickly than has ever been possible before, which can accelerate drug discovery in several ways—for example, from identifying novel drug targets and potential drug candidates to identifying promising candidates for further development. “AI can also help streamline the drug development process by identifying potential safety issues and predicting how drugs will behave in the body. This can help reduce risks to trial participants, and the number of failed or aborted trials,” he adds. “It can assist in designing and optimizing drugs by predicting their properties, such as solubility, bioavailability, and toxicity. This can help drug developers make more informed decisions about drug design, leading to more effective and safer drugs.”

AI has become more than just an automation solution, in the words of Berger. “AI-powered capabilities, including pattern recognition and evolutionary modeling, are essential to gather, normalize, analyze, and harness that growth and fuel modern therapy development,” she says. “AI has many applications across the full drug development value chain. In pre-clinical R&D, AI is being used to identify novel drug candidates without the need for traditional wet chemistry. In clinical research, AI innovations are driving transformations in clinical trial execution, including improved trial design, the development of novel digital endpoints, and the use of real-world data to identify optimal research sites and patient populations.”

In terms of OOC, Kostrzewski reveals that it is possible to reap immediate benefits by integrating computational in-silico tools. “There are three obvious opportunities, firstly the use of in-silico modeling upfront to inform drug design. By doing so companies can reduce the numbers of molecules that need to be screened. This opens up the opportunity to use more predictive human organ assays, such as OOC, earlier in the development process and speeds up the hit to lead process,” he explains. “The second use of in-silico modeling for [DOE] ahead of OOC to identify the right parameters to test, or to ascertain a concentration range for target engagement in an OOC model that is human-relevant. Following an OOC screening study, in silico physiologically based pharmacokinetic [PBPK] modeling can then be used to extrapolate data to predict the human response for ultimate data translatability. Overall, this combined approach provides significant accuracy and efficiency gains and with addition of AI and machine learning the data generated from many OOC studies could be combined and used to help further predict human responses to different interventions and therapeutic treatment regimens.”

There are some approaches, solutions, and technologies already available that can help jumpstart a drug developer transition to a more agile and flexible way of working. For example, single use and continuous processing together are increasingly used in manufacturing facilities, which Jones explains enables manufacturing facilities to “pop-up” as needed with very little required infrastructure to house equipment.

“The single use aspect of continuous processing reduces batch-to-batch cross contamination, as well as providing a built-in sterile manufacturing environment. Prepacked columns are a great compliment to this type of manufacturing model, given that they are equipped with the features necessary to plug and play into continuous process systems, and as mentioned previously, provide consistent results and stringent quality controls,” Jones says. “I expect that we will see continued advancements in the use of AI in prediction software geared towards all aspects of the drug development process, including the prediction of purification processes.”

Additionally, more and more developers are reaching out to CDMOs to complement in-house competencies and resources, as it gives them a more flexible approach, remarks Lee. “This is especially true in the early stages of development, where CDMOs with wide-ranging expertise and techniques can enable a higher probability of achieving the target product profile,” he says. “Knowledge and experience with multiple delivery routes can help identify the most effective delivery system, then during scale-up, leveraging a CDMO can reduce risk, expense, and timescales of in-house investment.”

Real-world data has gained significant momentum in drug development, enabling sponsors to harness insights that were previously unavailable to support their product development and positioning. Berger raises the point that tokenization is well established in the commercial setting as a way of accessing multiple data sources for insights.

“However, clinical trial tokenization, which links patient-level data from diverse sources without compromising patient privacy and allowing sponsors to incorporate real-world data into clinical trial analysis and gain a comprehensive picture of the patient journey across the healthcare system and into the follow-up stage, has not yet been widely adopted,” Berger adds. “Both large pharma and biotech companies are exploring, piloting, and evaluating the potential of this solution which combines technology, data, and analytics and delivers valuable insights. If adopted widely, our approach to clinical development could be transformed.”

Conroy, D. Accelerating Drug Development to Keep Pace with Drug Discovery. 

Agrawal, G.; Keane H.; Prabhakaran, M.; Steinmann, M. 

The Pursuit of Excellence in New-Drug Development

. McKinsey & Company, Article, Nov. 1, 2019.

Kronbetter, L.; Khaled, S. (2023) Refining Process Separation Procedures with Prepacked Chromatography Columns. International Labmate, Article, April 12, 2023.

Baillie, K.; Mueller, T.; Pan, J.; et al. Use of Record Linkage to Evaluate Treatment Outcomes and Trial Eligibility in a Real-World Metastatic Prostate Cancer Population in Scotland. Pharmacoepidemiol Drug Saf., 2020, 29 (6), 653–663.

Hurtado-Chong, A.; Joeris, A.; Hess, D.; Blauth, M. Improving Site Selection in Clinical Studies: A Standardised, Objective, Multistep Method and First Experience Results. BMJ Open, 2017, 7 (7), e014796.

Getz, K. Enrollment Performance: Weighing the “Facts.” 

When referring to this article, please cite it as Murphy, J. 

Moving Closer to Dynamic Drug Development

Articles

Cover Story

Hope is on the horizon as novel solutions and improvements aimed at benefitting the drug development process with the right framework are coming to the fore.

Moving Closer to Dynamic Drug Development 

Continued development of new and next-generation antibodies is spurred by the increasing demand for more effective and custom-tailored biologic therapies. While the bio/pharma industry is seeing a shift toward personalized medicines, ongoing work in research and drug discovery is generating new biologic modalities, such as next-generation antibodies.

In particular, bispecific antibodies are next in line after the decades of success that monoclonal antibodies (mAbs) have had in the industry. Bispecifics were mainly developed for cancer treatment, notes Luca Varani, PhD, Structural Biology group leader at Switzerland’s Institute for Research in Biomedicine, and founder of CLBiotech, a 2022 start-up company focused on nanobody engineering.

Bispecifics (and beyond that, multispecific antibodies) can be simply viewed as a cocktail in a single molecule, or rather, the concept is that of a single molecule that has the property of a cocktail drug. However, Varani emphasizes, bispecifics can do things that a conventional cocktail drug cannot, and that is, bispecifics act synergistically. This is considered a novel mechanism of action, he notes. 

“Bispecifics can achieve molecular functions that are not achievable by monoclonal antibodies,” Varani says. “If you think strategically, you could design a bispecific that acts like a cocktail.”

Ideally, Varani, says, a developer would want to look for bispecifics that do something that monoclonals cannot do, such as, for instance, having a bispecific that bridges two molecules on different cells. Or, another example could be using bispecifics to bridge different viruses, which would cause aggregation with the end result being that the virus is neutralized. Yet again, bispecifics can be used to bridge immune cells, such as T cells, to cancer cells.

“You attach the cancer cell on one end, and you bring the T cell immune system against the cancer with the other,” Varani demonstrates. “You cannot do that with a cocktail.”

Bispecific antibodies present challenges in downstream processing due to “shuffling.” To demonstrate this phenomenon, Varani says to imagine the antibodies having hands. In the case of a mAb, there are two hands. In the case of a bispecific or multispecific antibody, there are four or more hands. Shuffling occurs when the “left hand” of antibody 1, for example, binds with the left hand or the right hand of antibody 2. “This is a mess,” Varani asserts. “This complicates production purification, and you thus have to remove the forms that you do not want.”

“On COVID, for instance, I worked on bispecific [production]. It’s a human format. It’s identical to a monoclonal, but it is bispecific [in function]. Bispecific production yield was very low. Although the cost of production of bispecifics has gone down [significantly], there are still regulatory costs,” Varani says.

“Do you really have a bispecific? Are you producing a molecule that hits both its targets simultaneously? Does it remain a bispecific or does it open up once inside the body, how stable is it? These are all questions for which molecule characterization must be done,” Varani adds.

It is much more difficult to remove unwanted forms due to shuffling in bispecific antibody production compared with mAb production. Because shuffling must be avoided, product yield consequently tends to be lower, Varani says.

Although the purification process has since been improved, Varani notes that some trace amounts of unwanted bispecific antibody forms may be left behind. To that end, the more effective solution to minimizing shuffling and the formation of unwanted product is in the upstream, with molecular engineering, or rather, antibody engineering.

There are a number of solutions that can be derived through engineering. For example, one can engineer what’s known as “single chains” wherein a bispecific antibody can be forced into a single-chain format (rather than a folded molecule, the natural state of an antibody). “This is something very elegant,” Varani says. “You change the interface between heavy and light chains between the two hands [of the antibody] so that they are complementary to each other.”

Looking beyond bispecific antibodies, a new subcategory of antibodies is rising through the ranks: single variable domain on a heavy chain (VHH) antibodies, otherwise known as nanobodies (1), which are derived from camelids (e.g., llamas, alpacas, camels, etc.). One advantage that VHH antibodies hold is that they are single-chain antibodies, making them less structurally complex and smaller in size than human double-chain antibodies. Being single chain, VHH antibodies are not subject to shuffling, making their production much easier, according to Varani. Their small size and simpler structure also make them extremely stable.

In discussing the potential of VHH antibodies to act as immunotherapeutic agents, Varani says: “Being smaller, they have a much higher penetration in tumors. They get in much better than [conventional] antibodies. They can pass biological barriers as well, such as the blood-brain barrier.” Passing through the blood-brain barrier is a task that conventional antibodies cannot do. So, Varani explains, if conventional antibodies are injected into the blood, less than 1% of them will reach the brain, making them ineffective in treating neurological disorders, for instance. The supposition, then, is that VHH antibodies may have the ability to reach targets that conventional antibodies cannot reach.

However, with the pros come the cons. One major disadvantage that VHH antibodies have is that they have a much shorter half-life in vivo, Varani points out. Therefore, duration in the patient’s body may not be sufficient to confer full therapeutic benefit. “They have some advantages, but they also have some problems,” Varani states.

Yet, in the search for next-generation antibodies, VHH antibodies still hold strong potential. According to Varani, development work for VHH antibodies is currently booming after seeing flat activity prior to 2020, and clinical trial programs are in the pipeline. Importantly, the first VHH antibody product, Nanozora (anti-tumor necrosis factor alpha Nanobody), was approved in Japan in September 2022 for treating rheumatoid arthritis (2). Taisho Pharmaceutical developed Nanozora in Japan under a license agreement with Ablynx, a Sanofi company (2).

1. Bever C. S.; Dong J. X.; Vasylieva N.; et al. VHH Antibodies: Emerging Reagents for the Analysis of Environmental Chemicals. 

 (22), 5985–6002. DOI: 10.1007/s00216-016-9585-x
2. Taisho Pharmaceutical, Notification of Approval to Manufacture and Market Nanozora 30mg Syringes for S.C. Injection, a Therapy for Rheumatoid Arthritis, in Japan Japan’s First Nanobody Therapeutic. Press Release, Sept. 26, 2022.


Volume 36, No. 6
June 2023
Pages: 15–17

When referring to this article, please cite it as Mirasol, F. Pushing the Barriers in Next-Gen Antibody Development. 

Development

New fields are being explored to bring novel antibody candidates to the pipeline.

Pushing the Barriers in Next-Gen Antibody Development

While the biopharma industry is pushing the barriers with antibody development, it must also contend with contemporary challenges in bulk monoclonal antibody (mAb) manufacturing. The need for good manufacturing practice compliance for mAbs going forward is increasingly crucial.

To highlight some of the bottlenecks and solutions in bulk mAb manufacturing, 

® spoke with Lee Seung-sun, lead scientist for the Manufacturing Science and Technology team at Samsung Biologics.

 What specific aspects in bulk mAb manufacturing are the most challenging?

 As intensified process and continuous process are on the rise, many products these days have high cell number and titer. As a result, perfusion has been introduced to N-1 or N stage of cell culture process, and process development has involved using more feeds in high concentration. 

Especially with mass production, companies, including Samsung Biologics, have operated with more trains for cell culture than for purification as the cell culture process used be the bottleneck. However, with a significant increase in titer these days, the purification process is becoming the bottleneck. Such changes accelerate transition to continuous processing and an automation platform.

As market demands for various types of modalities such as antibody drug conjugates (ADCs) are increasing, the traditional workflow process of cell culture to purification to fill/finish cannot thoroughly respond to the rapidly changing market. Continuous investment and rapid adoption of new technologies are required.

Since the COVID-19 pandemic has disrupted global supply chain, it has been hard to procure as much raw materials as required at the right time, and everyone is suffering from the prolonged situation. Especially for manufacturing of mAb drug substance, it is challenging to find the alternative to the raw materials that have been used, and, even if [alternatives are] found, it will take a considerable amount of time and effort to identify all risks related [to these alternatives] and introduce [them] to the actual manufacturing process.

 How much improvement in the overall mAb manufacturing process has resulted from the implementation of process analytical technology (PAT)?

 The use of various in-line sensors, including Raman, allows for more immediate responses to various issues during manufacturing, and better fine-tuning of the process itself compared to the past. People are getting more process knowledge as more data [are] acquired. However, to take full advantage of PAT, a system that can enable on-line and real-time use of information sensed by the in-line sensor needs to be established together, implying that an automated manufacturing facility that can be operated based on electronic batch records is required. This would be accompanied by large investment.

With the implementation of PAT, we are now in the process of transitioning from traditional process control to predictive process control, and the importance of data science has emerged in the biopharma industry accordingly. Establishment of a continuous process in an automated facility using PAT will enable manufacturing of high-quality mAb drug substance with much less time and cost, compared to the traditional manufacturing process. Samsung Biologics is in the process of digital transformation to keep up with these changes.

 What strategies have thus far been successful in improving process control over bulk mAb manufacturing?

 Time required for tech transfer and potential risks during engineering run and process performance qualification can be reduced by utilizing platform processes. Use of well-defined scale-down models and establishment of scale-down models with pilot scale can be alternatives to reducing risks for large-scale production. For commercialized products with a sufficient amount of historical data, data-driven improvement of process control can be done based on the historical data accumulated.

 What unmet needs still exist in bioprocessing (e.g., a technology, a piece of equipment, or an analytical requirement) that limit the ability to effectively control the mAb manufacturing process?

 Compared to other advanced manufacturing industries, the mAb manufacturing process is less automated and more labor intensive. Not only is it hard to predict and manage various issues that could potentially occur during the process, but it also takes significant amount of money, manpower, and time to find root causes of the issues and fix them.

 What other methods, or technology, or approaches can be used to further streamline the mAb manufacturing process (especially removing bottlenecking)?

 The mAb manufacturing process is in the process of eliminating bottlenecks through transformation into automated and continuous processes. The introduction of digital twins is expected to reduce time, manpower, and material spent on manufacturing in the near future.

When referring to this article, please cite it as Mirasol, F. Pulling Out All the Stops in mAb Manufacturing. 

Compliance with GMP standards remains an integral focus in bulk mAb manufacturing.

Pulling Out All the Stops in mAb Manufacturing

Over the past decade, a large portion of the resources dedicated to scientific research has been focused on solving widespread unmet medical needs. This is particularly true within cancer, where many patients have limited treatment options. One of the most promising treatment approaches, which is equally as complex as cancer, is cell therapy.

Cell therapies are an emerging modality that are accelerating at breakneck speed. In fact, FDA created an advanced therapies “super office” specifically focused on increasing the volume of reviews for the growing pipeline of cell and gene therapies. Since inception, only a handful of cell therapies have received FDA approval, but there are more than 1200 cell and gene therapies active in clinical trials (1).

As an approved treatment option, cell therapies are relatively new. Novartis’ Kymriah (tisagenlecleucel) was the first chimeric antigen T cell (CAR-T) therapy approved and came to market about five years ago in August 2017 (2). Now, there are seven FDA approved CAR-T drugs on the market, and while this is a major milestone in the history of cell therapy, these CAR-T drugs only cover a small percentage of global unmet medical needs.

Although cell therapy is a promising new modality, improvements in cost and efficacy are needed to unlock the treatment’s potential. The manufacturing process for early cell therapies is labor intensive, with multiple touchpoints. This often results in inconsistencies, contamination, and long throughput times, all of which contribute to subsequent safety concerns and failure modes, as well as the incredibly high costs that hold these therapies back from reaching wider patient populations and realizing their full potential.

Common recent strategies to overcome these hurdles in next-generation cell therapies involve the use of scaling up or out and working with alternative cell populations. Not surprisingly, these innovative workflows both introduce new challenges, such as maintaining performance at scale, and can exacerbate the existing ones if the process isn’t thoughtfully designed.

While it is true that most of the cell therapies in the market today were developed through academic manufacturing processes, the intrinsic challenges of cell therapy extend beyond commercial scaling.

The primary challenge is that peoples’ biologic makeup varies from individual to individual. Whereas many other recombinant protein-based therapies are manufactured using well-characterized cell lines derived from CHO cells that are predictable and enable consistent therapy manufacturing and, thus, consistent therapy performance, cell therapies are not created from well-characterized cell lines and the input material is different every time, yet the objective is still to deliver consistent output. When talking about autologous cell therapy (ACT) specifically, the patients’ cells are the input material into the therapy manufacturing process. This means that the quality of the donor cell material directly correlates to the quality of the output material, which is the therapy itself. Older patients and those that have been fighting challenging diseases often present with cells that are “exhausted,” which is to say they show less responsiveness to stimulation and, in turn, tend to generate weaker immune responses.

Efficacy is also a major challenge. In addition to concerns over the quality of the cellular input, the harsh conditions that immune cells can encounter in tumor microenvironments require that the cells be well equipped with “armoring and camouflage” to withstand the obstacles that prevent them from reaching their target, the tumor. When pursuing ACT, utilizing the patient’s limited number of high performing, qualitatively youthful cells to produce a therapy that is ineffective further limits the treatment options of patients who are already exploring final-resort treatments.

Overcoming these inherent challenges requires not only a considerable amount of expensive quality control, but it also requires adopting instrumentation and workflow processes that minimize the opportunity for failures that are costly—both in actual treatment expense as well as patient outcomes—and support efficiencies that address the critical cost and performance challenges.

With this in mind, significant progress has been made over the past five years to create innovations that accommodate closing, automating, and scaling the manufacturing process.

With the cell therapy market poised for rapid growth in the next decade, new technologies and evolutions in cell therapy manufacturing continue to support the commercialization of high-performing therapies and accelerate the development of the next class of cell therapy breakthroughs.

New innovations brought to market lower treatment costs and boost therapeutic performance by closing the cell therapy manufacturing workflow, thus minimizing manual touchpoints that lead to manufacturing failures.

Across every step of the cell therapy workflow—from collection and isolation, to activation, editing, expanding, and transporting—there are manual process or connection points that are susceptible to failure modes due to contamination or inconsistent practices.

Closing the workflow reduces manual interventions, decreasing the likelihood for human error or contamination to be introduced. When looking specifically at addressing this challenge, there are some steps in the cell therapy manufacturing process where technologies to remove human intervention do not exist. However, there are manual steps that are considered addressable, which characterizes process steps that have traditionally been conducted manually and can now be closed thanks to recent innovation. Cell isolation is one example of an addressable step. Cell isolation has been open and time consuming due to the collection and centrifugation steps, which were conducted manually and required significant repetition to produce a single therapy. Gene editing, whether transduction or transfection, is similar in that many steps have often been carried out by hand in the past. Other examples of steps that are still often open include sampling, though in-line monitoring and auto-sampling will solve this, media formulation, and quality control assays, which don’t affect the therapy itself but rather the treatment release timing and the cost in a major way.

Once the workflow is closed, automation can be introduced to further drive efficiency and help reduce costs. For cell isolation, technologies have been introduced that create an automated environment that consistently delivers greater than 86% isolation efficiency of target cells with 96% purity, all without impacting cell viability. In one specific case, high purity levels of >95% were achieved in a pre-clinical manufacturing workflow that initially struggled to reach cell purity levels higher than 40%. This same environment enabled a cell isolation protocol that can process up to 1 L volume (≥10 billion target cells) in approximately 70–100 minutes, which would historically take three to four hours on average (3).

Automation not only enhances efficiencies by reducing the need for highly skilled technicians to do repetitive tasks, but also increases cell therapy manufacturing success rates and reduces failures caused by contaminations introduced by human touchpoints. Examples where automation has been successfully implemented can be seen throughout these workflows. The most prominent example of this in cell therapy is in the expansion phase, specifically via the introduction of bioreactors, which have made it easy to manipulate the culture and eliminate a traditionally error-prone touchpoint, and manual interventions that have been necessary when using flasks, bags, and vessels. Bioreactors also enable physical connectivity between upstream and downstream steps involved in the process via liquid handling tools such as pumps, sensors, valves, and bubble traps. Cell processing, cell isolation, and genetic manipulation have also been plagued by a heavy amount of labor-intensive steps in the past, but more recent innovations have now made it possible to carry these steps out in a closed fashion as well. Other, less-universal examples of these automation-friendly innovations include solutions to automatically remove paramagnetic beads that are used for cell isolation and activation from the system, as well as the tools for auto-sampling and in-process monitoring.

The speed of manufacturing, which is critical for both therapy developers and patients, is also improved through automation. In studies, new instrumentation that automates the bead removal process delivered significant time improvement. In one case, the automated system accelerated the debeading process from two hours to 29 minutes, representing a 76% reduction, without impacting cell recovery (4) (

While these results are promising, it’s important to consider the approach to closing and automating a cell therapy manufacturing process. Unlike the production of mature modalities, such as monoclonal antibodies, the optimal workflow for the development of cell therapies has not yet been established. As therapy developers work toward closing their workflows and automating as many steps as possible, it’s becoming clear there are two distinct approaches. First, a more rigid approach that seeks to provide a walled off, all-in-one, single solution. The aim here is the create speed and scale by having fixed protocols for each step in the process. The second approach is more modular and focuses on delivering flexibility at each step within the workflow. The sentiment in this second approach rests on the notion that flexibility allows therapy developers to use protocols and instrumentation that best suit a specific workflow for a specific therapy and allows for more in-process adjustments to cater to donor variation. While both approaches are viable, given that scale of manufacturing is going up (allogeneic) and going down (autologous), a modular approach appears to best support a wider range of cell therapy manufacturers pursuing various workflows by giving them the ability to adapt and continue advancing their therapies, whereas the more rigid, singular approach limits their overall flexibility and ability to pivot when necessary.

In parallel to closing the cell therapy manufacturing workflow, tactics to simplify the manufacturing process continue to be explored. In 2022, Novartis showed that they could exclude the expansion process and dramatically simplify the process. By transferring the cell therapy drug to the patient for in-vivo cell expansion, the company shortened this process from 10–14 days down to as little as 24 hours (5).

While the need for closing cell therapy workflows and automating the manufacturing process is apparent, the path forward for advancing cell therapy development remains open for innovation. It is not expected that one approach for cell therapy manufacturing will become ubiquitous; there is a place for allogeneic and autologous, but the infrastructure to support both modes of manufacturing will continue to evolve. With allogeneic manufacturing, scaling the cultivation of donor cells will be immensely important to resolve the economic challenges and make this approach viable long term. For autologous, scaling out the manufacturing process, rather than scaling up the size of batches, is the key. This is where the centralized versus decentralized manufacturing infrastructure debate stems from.

Traditionally, centralized manufacturing of just about anything was the most efficient approach. However, when the product being produced is a biologic therapeutic, additional challenges are introduced. Transportation and logistics, including the regulations that come along with it, make an already complex treatment process even more convoluted. Because of this, the prospect of simplifying delivery through decentralized manufacturing is appealing. Technologies exist to be able to build autologous cell therapy manufacturing at a suitable scale at each of the major oncology institutions across the world. However, the technology for quality control processes is still lagging, which is hindering the buildout of decentralized cell therapy infrastructure.

No matter the manufacturing approach, greater connectivity and integration—both physical connection of instruments and digital connection for data transfer—will help support the next generation of cell therapy manufacturing. Connectivity will help mitigate the variation that is inherent in cell therapy manufacturing. While having a standard workflow is essential for efficiency and scaling, developing an extremely rigid cell therapy workflow can lead to failures due to the large donor-to-donor variations. A modular platform, with closed processes and integrated data sharing will support manufacturing optimization on the fly.

The pace of innovation within the cell therapy space has been awe inspiring. While there are more challenges to be overcome, momentum is already being translated into impact, and there are many reasons to remain optimistic about the modality’s potential in the future.

1. Mikulic, M. Number of Cell and Gene Therapy Clinical Trials in the Global Pipeline as of 2022, by Indication. 

, Nov. 23, 2022.
2. Novartis, Novartis Receives First Ever FDA Approval for a CAR-T Cell Therapy, Kymriah (CTL019), for Children and Young Adults with B-cell ALL that Is Refractory or Has Relapsed at Least Twice. Press Release, Aug. 30, 2017.
3. Thermo Fisher Scientific, 

Achieving High Purity with the CTS DynaCellect Magnetic Separation System

. Case Study report (2023).
4. Thermo Fisher Scientific, 

Streamlining Cell Therapy Manufacturing with Rapid and Reliable Bead Removal

. Case Study report (2023).
5. Penn Medicine, Penn Researchers Shorten Manufacturing for CAR T Cell Therapy. Press Release, March 29, 2022.

Evan Zynda, PhD, is senior scientist at Thermo Fisher Scientific.


Volume 36, No. 6
June 2023
Pages: 26–29

When referring to this article, please cite it as Zynda, E. Addressing Cell Therapy Challenges Through a Modular, Closed, and Automated Manufacturing System. 

Manufacturing

Scaling cell therapy production workflows requires the establishment of closed, automated steps.

Addressing Cell Therapy Challenges Through a Modular, Closed, and Automated Manufacturing System

A crucial step in achieving approval of a biosimilar is establishing analytical and clinical biosimilarity with the innovator biologic (i.e., reference product). Analytical biosimilarity studies therefore aim to demonstrate a highly similar profile taking into account variations in critical quality attributes (CQAs) of the biosimilar product. Such variations, however, must fall within a range set by the innovator.

Biosimilarity studies should consist of detailed comparative structural and functional characterizations, the data for which must be gathered using appropriate, validated analytical methods. These analytical methods must not only fingerprint the molecule in question but must also help reduce the cost (economic burden) that would otherwise be incurred in meeting regulatory requirements for extensive preclinical/clinical similarity data (1). In reducing cost at the biosimilarity study stage, it makes sense that the biosimilar product can thus be more affordable than its innovator.

Luckily for the biopharma industry, biosimilar manufacturing processes and the regulations associated with getting approval for them have become more well established in the past decade, as evidenced by the number of biosimilar drug approvals during that timeframe. It has also been helpful that biosimilarity studies that have been conducted (with an eye toward gaining regulatory approval) are being published more frequently and being made public, making access easier. As a result, some technical advancements that have been made in analytical sciences have found their way into techniques used for biosimilar assessment (1).

® delved into the challenges and advancements made in analytical methods for biosimilar characterization with Stephen Pagnotta, executive director and biosimilar commercial lead at Boehringer Ingelheim.

 What is meant by ‘implementation of orthogonal tools’, and why are orthogonal tools important for biosimilar studies?

 Orthogonal tools or techniques are laboratory methods used to characterize the structure of a molecule or protein. To build a complete physiochemical profile of a biotherapeutic, multiple orthogonal assessments are used to capture different aspects of a molecular structure. These techniques include, but are not limited to, peptide mapping, mass spectrometry, circular dichroism, and analytical ultracentrifugation.

Orthogonal tools are important for biosimilar studies because researchers must establish that the biosimilar is structurally like the reference product so that there is no clinically meaningful difference in terms of safety, efficacy, purity, and potency.

 What analytical advancements have been made that have boosted the ability to conduct biosimilar studies?

 Biosimilar development requires extensive analytical comparison of medicine structure and function to ensure biosimilarity to the reference product. Analytical method development is a procedure for reliable detection of analytes of interest. High-grade method development ensures that the method is suitable for full validation and high-quality analysis of medicines, metabolites, and biomarkers in biological matrices. Advances in analytical techniques have resulted in more rapid results, increased reproduction validation, and higher selectivity and specificity.

During research, the developed analytical methods are utilized to measure and define the required dosage, acceptable impurity, observed stability, and bioavailability of the medicine overall.

 Why is it so challenging to demonstrate biosimilarity with respect to CQA variations between the biosimilar product and its innovator?

 Biotherapeutics are more structurally complex compared to small-molecule medicines, and this complexity requires manufactures to use advanced analytic methods to verify structural similarity between the biosimilar and its reference product.

 Industry dialogue revolves around the two concepts: biosimilarity and interchangeability. What are the differences between the two terms and what is the impact on a biosimilar product’s trajectory on the regulatory pathway to approval?

 A biosimilar is a version of a biologic medication that is made by a different company than the one that invented it, with no clinically meaningful differences in terms of safety, potency, and purity.

An interchangeable biosimilar first must meet the high FDA standards of a biosimilar. Then, to achieve the interchangeable designation, the biosimilar must be supported by additional FDA-required data, generally through one or more studies of multiple substitutions in patients, known as an interchangeability study.

An interchangeability study shows how patients do when they are switched back and forth from a reference product to the interchangeable biosimilar. The interchangeability study is designed to demonstrate that patients can be switched with no increased risk in terms of safety or diminished efficacy, as compared to remaining on the reference product. The FDA interchangeability designation enables auto-substitution at the pharmacy level. Individual state laws control how and whether providers must be notified.

 Why is it important to develop new analytical methodologies not traditionally used in biosimilar studies?

 Biosimilar development follows the regulatory authority guidelines such as those from the FDA and EMA [European Medicines Agency]. As the number of medicines released in the market is increasing by the day, so is the need for method development and validation. These new medicines may be compounds never used before or modifications of existing medicines. An inability to relay analytical procedures, as well as reference and internal standards for new medicines, could hinder thorough R&D. Hence, it becomes necessary to develop new analytical methods for studying the effect of medicinal compounds. These methods are designed to understand the identity, characteristics, purity, and potency of medicinal compounds.

1. Nupur, N.; Joshi, S.; Gulliarme, D.; Rathore, A. S. Analytical Similarity Assessment of Biosimilars: Global Regulatory Landscape, Recent Studies and Major Advancements in Orthogonal Platforms. 


Volume 36, No. 6
June 2023
Pages: 30–31

When referring to this article, please cite it as Mirasol, F. Assessing Biosimilarity with Analytical Advancements. 

Analytics

Analytical characterization of biosimilars plays a crucial role in a successful path to regulatory approval.

Assessing Biosimilarity with Analytical Advancements

Since the beginning of the COVID-19 pandemic, providers offering contract testing services have seen various changes and improvements to everyday processes. According to Lara Silverman, PhD, founder and principal consultant at LIS BioConsulting, it became increasingly crucial for contract testing labs to provide seamless services to clients and communicate any issues in a quick, efficient fashion. Dana Cipriano, senior vice-president of Testing & Analytical Services at the Center for Breakthrough Medicines, seemed to second this observation, sharing that she has seen contract testing services demonstrate a major increase in the speed and efficiency of testing using new testing methods and technologies.

Some other new processes that have occurred in the bioprocessing/testing services space include new analytical technologies for fast in-process controls during virus-like particle production, according to Nik Barbet, PhD, head of Operations at Vector BioPharma. At Eurofins BioPharma Product Testing, Stanley Prince, Director of Biosafety & Cell/Gene Therapy Strategy, said they are focused on investing in automation and alternative methods and technologies, such as the RNA-based BioFire rapid mycoplasma test. Additionally, a proprietary degenerate polymerase chain reaction platform used to offer services for rapid detection of adventitious contaminants (Blazar®), as well as rapid sterility testing with an emphasis on services are emerging from MilliporeSigma, where the company is focused on adopting rapid molecular and genomic methods, according to Benoit Gourdier, head of Contract Testing Services at MilliporeSigma.

With these analytical testing services, bio/pharma companies are still benefitting in terms of cost savings and efficient development times. Outsourcing analytical testing to contract testing companies helps to reduce the cost of drug development by providing access to state-of-the-art equipment and expertise and reduces the time required for drug development, according to Cipriano.

Shailesh Vengurlekar, senior vice president, Quality & Regulatory Affairs at LGM Pharma, added that a lot of small- or medium-sized companies do not have enough qualified lab chemists, space, or equipment to meet their internal need of analytical method development and validation.These companies compete directly with larger organizations for on-time product approval and market share. However, the expense of testing facilities and qualified staff, along with regulatory costs, can be outrageous. By contracting analytical services, these companies can redirect their core competencies to meet company goals on time.

Barbet, meanwhile, explains how emerging analytical technologies require highly specific expertise, skills, and occasionally equipment that are not always easy to establish internally. As a result, corresponding services that are contracted with recognized service organizations are needed to solve technically demanding tasks.

In terms of upcoming changes to testing services from contract development and manufacturing company/contract manufacturing company (CDMOs/CMOs), although there are shifts happening, it can take time to onboard and prepare an outside testing provider, according to Silverman. “Instead, if internal capabilities exist, that process could be
streamlined and therefore reduce cost to the customer and overall timelines. Also, for cell therapy products, specifically, where lot sizes can be very small, some of the major providers of testing services are unfamiliar with how to manage small lot sizes, which can cause delays as the team defines a sampling strategy to meet existing internal qualifications of tests,” she said.

Increasing the testing services offered for biologics, including characterization and stability, adds value for customers, Vengurlekar said.

Stability testing has been and will continue to be required for all drug products, including biologics, and according to Gourdier, they will assess both drug substance and drug product for attributes, such as potency and degradation at long term and accelerated storage conditions, sensitivity to heat, light, and humidity, and freeze-thaw viability.

As for the future of contract testing services and their impact on the industry, people such as Barbet hope that services for transducing particle quantification or for genomic purity and vector integrity will boost the demand for external testing services, especially for gene therapies. Prince explained that many organizations are attempting to still follow the traditional compendial approaches and guidance documents that were intended for biologics, where volumes and product concentrations are not an issue. As this industry continues to grow, Vengurlekar believes that—as new technologies are introduced—CDMOs can embrace the change and adopt these shifts into their service line offerings.

Silverman highlighted how important contract testing services are to the industry in helping enable drug developers to bring novel products to patients. She hopes that contract testing labs are prepared to understand new modalities and provide meaningful technical insight and regulatory advice to cutting-edge companies. “Following approvals, testing laboratories must be ready to support the potential high volumes and fast turn-around times during commercial use, which means building a strong relationship with the drug developer and preparing capabilities to support product release in a timely manner. For some patients, these products are lifesaving and delays are simply unacceptable,” she asserted.

Contract Testing Services Solidify Their Place in the Manufacturing Value Chain

Outsourcing

Contract testing services demonstrate a major increase in the speed and efficiency of testing using new testing methods and technologies.

Contract Testing Services Solidify Their Place in the Manufacturing Value Chain 

The continued surge in applications to FDA for testing new gene therapies is taxing the agency’s resources and highlighting the need for new policies and updated operations to fully realize the promise of these cutting-edge treatments. FDA authorized accelerated approval for a new amyotrophic lateral sclerosis (ALS) treatment, Biogen’s Qalsody (tofersen), based on years of testing to demonstrate the drug’s potential for blocking production of a protein believed to give rise to ALS in some 500 of approximately 30,000 ALS patients with a specific gene mutation (1). Meanwhile, bluebird bio is seeking approval of a new treatment for a certain form of sickle cell disease (SCD), a lovo-cel gene therapy that is injected into the patient’s blood to produce anti-sickling hemoglobin (2).

To further such advances, officials in the Center for Biologics Evaluation and Research (CBER) seek added resources and new approaches for quickly bringing innovative therapies to patients. In numerous presentations in recent months, CBER Director Peter Marks has lamented the slow pace and high cost of developing and testing new gene therapies. FDA has approved about a dozen of these cutting-edge treatments so far, he pointed out in a webinar on April 4, 2023 sponsored by the Alliance for a Stronger FDA (3). But after two decades of effort in this area, he urged changes to approve more than a handful of new products each year. “I don’t think we have a really long time to play around,” Marks commented, but need to “transform the environment” for developing these treatments through accelerated endpoints and regulatory flexibility.

One recent change is the formation of a new “super” Office of Therapeutic Products (OTP) in CBER to replace the smaller Office of Tissues and Advanced Therapies (OTAT). OTP has six offices overseeing 14 divisions and 33 branches, designed to house an expanded staff able to quickly assess new research programs and steer promising therapies through the regulatory process. The latest version of the user fee program for drugs and biologics provides added funding to support an increase in experts assigned to gene therapies, advanced manufacturing technologies, and related programs (4).

Marks also has proposed that CBER adopt some of the innovations established by FDA’s Oncology Center of Excellence (OCE), including FDA’s accelerated approval pathway for promising therapies. While acknowledging that not all fast approvals will confirm benefits later, he is optimistic that this approach can provide many seriously ill patients with access to important treatments faster than otherwise. A related plan is to launch a new version of Operation Warp Speed for rare diseases to support the development of gene therapies for conditions affecting small patient populations, starting with a few high-need programs that could benefit from more constant contact with FDA. The tension between approving a potentially important new therapy for children with a debilitating rare genetic disease based on preliminary evidence, or waiting for further clinical trials to confirm benefits, was paramount in the recent debate over accelerated approval for Sarepta’s new treatment for Duchenne muscular dystrophy, which an FDA advisory committee approved by a close 8–6 vote last month.

In addition, CBER is working to advance international cooperation among regulatory authorities in vetting and regulating new gene therapy applications to expand the global pool of patients testing and receiving treatment. This involves applying elements of OCE’s Project Orbis program to provide a framework for regulators to cooperate in reviewing concurrent submissions for biotech products outside the oncology area.

The high cost of producing gene therapies for small patient populations, however, presents the highest hurdle for CBER and manufacturers to bring more innovative gene therapies to patients. While FDA doesn’t consider cost in assessing the safety and efficacy of a medicine for market approval, Marks has voiced concerns about the long timeframe and expensive
methods for producing treatments for only 30 to 40 patients a year—a process that he recognizes is very different from manufacturing monoclonal antibodies for thousands of people. Some gene therapies make it through clinical development, he noted, only to be dropped by sponsors due to high production costs that make these new treatments “commercially non-viable” and put clinical trial sponsorship out of reach of small companies and nonprofit disease organizations and foundations.

A priority for Marks is to reduce the bottlenecks in gene therapy production processes and to provide added assistance to sponsors struggling with manufacturing issues. The expanded OTP has three chemistry, manufacturing, and controls (CMC) offices—for gene therapy, cell therapy and human tissue, and for plasma protein therapeutics—to accommodate more staffers with expertise in biotech manufacturing able to provide timely, accurate information in this area.

CBER also has scheduled virtual “town hall” meetings for OTP staffers to clarify expectations on specific technical components required for investigational and market applications for cell and gene therapies. At presentations in September 2022 and in April 2023, reviewers from OTP’s Office of Gene Therapy CMC addressed questions on guidance documents, assay qualification and validation, product characterization and release testing, and stability studies at different stages of product development and use (5). Another session on June 8, 2023 will focus on CMC for cell and tissue products (6).

Marks sees a two-to-three-year window to move forward and transform the environment and manufacturing process for gene therapies. Under current methods, these new products will continue to raise challenges in the cost and pricing arena, as seen in Biogen’s price tag for its new ALS drug of almost $200,000 a year for treatment. “If we get it right,” Marks says, FDA will realize some of its goals for advancing gene therapies, which will make a “huge difference in the bio-economy,” while also impacting patients’ lives sooner.

FDA Approves Treatment of Amyotrophic Lateral Sclerosis Associated with a Mutation in the SOD1 Gene.

bluebird bio. bluebird bio Submits Biologics License Application (BLA) to FDA for lovotibeglogene autotemcel (lovo-cel) for Patients with Sickle Cell Disease (SCD) 12 years and Older with a History of Vaso-Occlusive Events. Press Release. April 24, 2023.

Alliance for a Stronger FDA Webinar with Dr. Peter Marks, Director of the FDA Center for Biologics Evaluation and Research. April 4, 2023.

FDA. Establishment of the Office of Therapeutic Products. 

OTP Town Hall: Gene Therapy Chemistry, Manufacturing, and Controls–April 2023. Town Hall. 

OTP Town Hall: Gene Therapy Chemistry, Manufacturing, and Controls–June 2023. 

 Washington editor, jillwechsler7@gmail.com.

When referring to this article, please cite it as Wechsler, J. FDA Eyes New Strategies to Spur Gene Therapy Development. 

Regulatory Beat

An increase in applications for gene therapies is putting stress on FDA’s resources.

FDA Eyes New Strategies to Spur Gene Therapy Development

Pharmaceutical manufacturers strive to address many concerns including cost and lead times in the supply chain. “Speed to market remains a top priority with our clients,” says Kristin Smith, client coordinator at Sharp. Other concerns include compliance with stringent quality control requirements and delivering on sustainability commitments.

Outsourcing operations, especially packaging, addresses these priorities and generates many benefits for pharmaceutical manufacturers. As a result, 60% of pharma manufacturers outsource at least a portion of their operations to a third-party contractor, according to 

2022 Pharmaceutical Manufacturing: Trends Shaping the Future

, a report published in March 2022 by PMMI Business Intelligence, a division of PMMI, The Association for Packaging and Processing Technologies. Driving forces behind the interest in outsourcing include the rise of injectables and personalized medicine and the accelerated pace of new product development, which has strained production capabilities for pharmaceutical manufacturers (1).

Packaging is often outsourced because of its complexity. Smith at Sharp explains, “Packaging involves a degree of technical, operational/process, and design complexity, which creates the need for ‘solutions’ providers … to manage packaging as a holistic process including design, engineering, packing, serialization and aggregation, foreign-trade zone, qualified person services and release, stability, and ID testing.” In addition, outsourcing can provide “a partner who can offer a breadth of regulatory and rapid launch requirements, including global regulatory requirements for multi-market launches.”

Contract packaging services provide numerous advantages for both clinical trials and commercial medicines. Contract packagers “can offer expertise, flexibility, and efficiency, while further mitigating risk and maintaining product quality and safety,” says Justin Schroeder, global vice-president of technical sales at PCI Pharma Services.

For example, “using a contract development and manufacturing organization (CDMO) allows companies to benefit from the expertise and specialized knowledge gained through handling a wide variety of products with varying parameters, such as ultra-low temperature handling,” says Harry Lindenmuth, vice-president operations at Almac Pharma Services, who oversees the company’s Audubon, Pennsylvania, site.

Smith at Sharp agrees, noting third parties often are chosen for therapies that require more complex handling, assembly, packaging, and storage requirements (e.g., cold chain, frozen storage, or high-value small-batch drugs). In addition, contract packaging organizations maintain a broad network of suppliers, including those who will collaborate on sustainable packaging efforts.

Reduced costs are a major benefit of outsourcing because manufacturers don’t need to purchase, install, and validate new equipment and lines, thereby freeing up capital and personnel for use elsewhere in the operation (1). Eliminating the need to invest in packaging equipment, labor, materials, and floorspace allows pharma and biotech companies to focus on their core competencies (drug development and manufacturing). This not only lowers costs but “also provides greater flexibility and scalability, enabling them to grow quickly and adapt easily to changes in demand,” says Lindenmuth. The outcome is improved supply chain efficiency and inventory management and reduced lead times.

Josh Goolcharan, director of sales and marketing at Reed-Lane, agrees, noting, not only are packaging activities outsourced but these partners are asked to manage the procurement of all necessary components. He says, “This allows customers to focus efforts more on marketing existing products and developing additional ones.”

Speed to market may be the biggest benefit of outsourcing pharmaceutical packaging. Outsourcing can deliver rapid launch support and/or launches in multiple markets across the globe and reduce risks by providing a deep understanding of up-to-date regulatory and compliance guidelines in multiple countries.

Outsourcing also can strengthen the supply chain and provide production redundancy. “Single sourcing is no longer a viable strategy when material and labor shortages persist in many countries,” explains Schroeder. He adds, “PCI and other CDMOs are organized and structured with flexible assets complemented by a network of locations around the globe to move quickly and operate with agility. [Service providers can also] increase speed by serving in a consultative advisory capacity, helping clients streamline their approach and avoid unnecessary steps.”

Engaging an experienced CDMO expands packaging options and enhances quality and efficiency because it provides access to knowledgeable teams, who routinely handle various types of pharmaceutical packaging. “Companies are provided with the surety that their packaging is performed correctly and consistently, and that processes, such as serialization, are performed to the highest level of compliance,” says Lindenmuth.

In short, “the right contract packaging organization can offer the experience, expertise, and technology to handle various packaging complexities,” says Smith. Wide-ranging expertise includes:

technical expertise, which accommodates a range of formats and environments such as precise vial labeling, assembly of pre-filled syringes and autoinjectors/pens, cold-chain/frozen storage, and protection for products with light/temperature/humidity sensitivities

operational expertise, which addresses speed-to-market requirements, strict quality control needs, and process efficiencies for multi-country launches, as well as scalability for growing or fluctuating volumes

Third-party contract packaging service providers can help save time and money. 

BioPharm International, June 2023

Moving Closer to Dynamic Drug Development

Pushing the Barriers in Next-Gen Antibody Development

Pulling Out All the Stops in mAb Manufacturing

Addressing Cell Therapy Challenges Through a Modular, Closed, and Automated Manufacturing System

Assessing Biosimilarity with Analytical Advancements

Contract Testing Services Solidify Their Place in the Manufacturing Value Chain

FDA Eyes New Strategies to Spur Gene Therapy Development

Generating Benefits with Outsourced Packaging

Vaccine Nationalism Escalating Risk

Media for Suspension-Based Viral-Vector Manufacturing

Strategies for Contamination Control

Governance of Future Pandemics